(1) Field of the Invention
The present invention relates to gabexate mesylate ointments which have no harmful effect such as stimulation or allergic development on the skin or mucosa, i.e. have a high degree of skin safety, and which contain gabexate mesylate with improved stability in an ointment base.
(2) Description of the Prior Art
Gabexate mesylate is a compound expressed in the following structural formula: ##STR1## It has a function to deactivate proteolytic enzyme (hereinafter referred to as protease), and is dissolved in a fructose solution or the like to be instilled for treating pancreatitis.
Gabexate mesylate has been used in recent years as ointment for preventing inflammation, erosion and ulceration of the skin, mucosa or tissue adjacent outlet positions of alimentary canal fistulas including an artificial anus.
Where there is trouble with the pancreas or the alimentary canal, it is sometimes necessary to directly discharge pancreatic juice and other digestive fluids and contents of the alimentary canal from the body (the abdomen). This is done through a so-called alimentary canal fistula.
Pancreatic juice contains protease to decompose protein present in foods in the alimentary canal but not to digest the alimentary canal per se.
At the outlet position of a fistula, however, the contents of the alimentary canal leak out and adhere to the skin at times, and the digestive fluids tend to contact the skin. As a result, body surfaces, particularly the skin, mucosa and tissue adjacent the outlet position of the fistula can be digested or eroded by the protein-decomposing function of protease. This leads to dermatitis, erosion or ulceration, and in serious cases to peritonitis.
Among the alimentary canal fistulas, pancreatic and small-intestinal fistulas are most vulnerable to the action of protease. Apart from these, not only a fistula connected to an upper part of the large intestine but a fistula (or an artificial anus) connected to a lower part thereof is subjected to the influence of protease which has not lost its activity. Where such a fistula must be used over a long period or for life, dermitis, erosion or an ulcer will develop on abdominal skin, mucosa or tissue.
From this point of view, gabexate mesylate which is a protease-deactivating substance is used for preventing decomposition of protein in abdominal surfaces. Excellent results are obtained by applying a gabexate mesylate ointment to positions adjacent the outlet of an alimentary canal fistula.
Other types of inflammation also result from the action of protease. The gabexate mesylate ointment is therefore used in the treatment of a trauma, in a postoperative treatment, and in the treatment of dermitis, erosion or an ulcer, or applied to a position of skin trouble where mucosa is exposed and an exudate is present. The gabexate mesylate ointment thus applied is known to produce excellent results by suppressing the activity of protease and thereby mitigating the traumatic pain.
While gabexate mesylate is very effective in the treatment of various troubles, this substance is extremely unstable and readily becomes decomposed when heated. The decomposition is greatly expedited particularly in the presence of moisture, such as in humid atmosphere.
There is thus a problem in long-term stability (storage life) of the gabexate mesylate ointment having gabexate mesylate contained in the ointment base. For this reason the gabexate mesylate ointment is not commercially available. Currently the gabexate mesylate ointment is prepared according to prescriptions as necessary in hospital dispensaries or the like.
The ointment is prepared by using gabexate mesylate intended for injection purposes (with 100 mg of gabexate mesylate and 200 mg of an excipient in 1 vial). The ointment base often consists of Macrogol Ointment, boric acid and zinc oxide ointment, or Azunol Ointment (manufactured by Nippon Shinyaku Co., Ltd., Japan).
This gabexate mesylate ointment must be prepared according prescriptions in hospital dispensaries every now and again, which is very troublesome. Moreover, the gabexate mesylate ointment prepared as prescribed becomes decomposed during a use period and loses efficacy as days pass since no improvement has been made in the stability of gabexate mesylate in the ointment base.
There are Macrogol ointments of various molecular weights, and they may be mixed to form an ointment base having a viscosity suitable for intended purposes. On the other hand, this ointment base which is water-soluble is a main cause of the gabexate mesylate instability.
Attempts have been made recently to improve the stability of gabexate mesylate in the ointment base by adding ferric chloride to the Macrogol ointment base. It has been reported that an addition in 0.01% by weight of ferric chloride is effective to maintain stability at a storage temperature of 30.degree. C. for 6 months.
However, the Macrogol base used in the gabexate mesylate ointment is not suited for use from the point of view of skin stimulation and skin allergy. The addition of ferric chloride doubles stimulation of the body part to which the ointment is applied, especially mucosa, which poses a problem in the safety aspect.
The Macrogol ointment base is hydrophilic, and the ointment is not expected to remain on the position of application for a long time since it tends to be dissolved in and lost to sweat or the like. In addition, the hydrophilic ointment base is not expected to protect the position of application from digestive fluids (aqueous solutions). That is, the ointment base absorbs digestive fluids to become decomposed, whereby the digestive fluids contact the skin, mucosa and tissue.
In the case of a large-intestinal fistula (artificial anus), skin surfaces can be contaminated by colon and other bacilli. For the same reason as above, the ointment applied to the skin adjacent this fistula is ineffective to protect the skin from contact with contents of the alimentary canal.
It is also difficult to obtain an ointment having a required viscosity with an ointment base consisting of boric acid and zine oxide or Azunol Ointment of Nippon Shinyaku Co. Such an ointment base is undesirable since it causes, as does the ointment having the Macrogol base, allergy and stimulation of mucosa or an affected part such as an eroded part or an ulcer which in particular requires safety.
In order to solve the foregoing problems, the present inventor has carried out intensive researches for years on the relationship between the safety of gabexate mesylate and the ointment base.
It has now been found that white vaseline is most desirable from the point of view of safety to the skin and the like, and that gabexate mesylate is stable in white vaseline. However, an ointment base consisting of white vaseline alone is too viscous for the ointment to be applied appropriately. There is thus a problem relating to its handling.
The inventor then prepared a gabexate mesylate ointment by adding gabexate mesylate and a viscosity controller to the base consisting of white vaseline. Further researches have been conducted on the stability of gabexate mesylate in this ointment base.